The purpose of this project is to study mechanisms of formation of supersaturated gallbladder bile and to develop mechanisms for its prevention. This past year we have studied factors regulating the pool size of bile acids, which is one of the main regulating factors for bile saturation. We showed that the control of bile acid synthesis is probably a major factor determining pool size, but the rate of cycling of bile acids in the enterohepatic circulation may be another important factor. The latter may be influenced by the degree of absorption of bile acids in the proximal small intestine. It is well known that expansion of the bile acid pool with chenodeoxycholic acid (CDCA) will reduce bile saturation; however, we showed that in markedly obese subjects, CDCA treatment will not decrease saturation because of their elevated secretion of biliary cholesterol. Only during weight reduction will CDCA decrease saturation in obese subjects. Finally, bile saturation in certain disease states, such as diabetes mellitus and hyperlipidemia, can be increased, and therapy of these diseases can under certain circumstances enhance saturation and may thereby increase the risk for gallstone formation.